The present invention relates to ocular hypotensive agents or agents used for treatment of glaucoma which contains prostaglandins or 15-keto-prostaglandins, in which the carbon atom of the 20-position is substituted with a hydrocarbon group. Also, the present invention relates to ocular hypotensive agents which contain 13,14-dihydro-15-ketoprostaglandins.
Prostaglandins (hereinafter referred to as PGs) are the name given to the group of fatty acids which show various physiological activities and contained in human and animal tissues and organs. PGs essentially contain the prostanoic acid skeleton of the following formula: 
and some synthetic products may contain the above skeleton with some modification.
PGs are classified into several types according to their five-membered ring, for example, 
prostaglandins of the A series (PGAs): 
Prostaglandins of the B series (PGBs): 
Prostaglandins of the C series (PGCs): 
Prostaglandins of the D series (PGDs): 
Prostaglandins of the E series (PGEs): 
Prostaglandins of the F series (PGFs): 
Prostaglandins of the J series (PGJs):
and the like. Further, they are classified into PG1s containing 5,6-single bond: 
PG2s containing 5,6-double bond: 
and PG3s containing 5,6-and 17,18-double bonds: 
PGs are known to have various pharmacological and physiological activities, for example, vasodilation, induction of inflammation, platelet aggregation, contraction of uterine muscle, enteron contraction and the like. However, PGs also possesses various other activities, therefore there are some problems to use them as medicines. That is, when PGs are administered to obtain a single pharmaceutical activity, they often exhibit other activities as side effects. Accordingly, the investigations of PGs as a medicine have aimed to enhance the emergency of the main pharmaceutical activity. However, these investigations have been insufficient.
Among PGs, for example, PGAS, PGDS, PGEs, PGFs are known to possess ocular hypotensive potency.
For example, there is described in Japanese Patent Application KOKAI No. 1418/1984 claiming a priority based on U.S. Ser. No. 374165 (1982) by Laszlo Z. Bite that PGF2 has a high ocular hypotensive activity, and 15-keto-PGF2 has also it though a very little; and further in Japanese Patent Application KOKAI No. 66122/1988 claiming priorities based on three U.S. Ser. Nos. B39056 (1986), 892387(1986) and 022046 (1987) that PGA, PGB and PGC can be used for a treatment of glaucoma.
However, when topical application of these PGs, topically to rabbit eyes, they are accompanied with transient ocular hypertensive response, and still pronounced conjunctival and iridal hyperemia, and further side effects such as lacrimation, eye mucus, lid closure and the like are observed. Accordingly, there are some problems when PGs are used as remedies for glaucoma or ocular hypotensive agents.
On the other hand, PGs wherein the carbon atoms at the 13-14 positions are saturated and the carbon atom at the 15 position forms a carbonyl group are found to exist in human or animal metabolites. These 13,14-dihydro-15-keto-prostaglandins (hereinafter referred to as 13,14-dihydro-15-keto-PGs) are known to be naturally produced metabolites by enzymatic metabolism of the corresponding PGs in vivo. These 13,14-dihydro-15-keto-PGs have been reported to hardly exhibit various physiological activities that PGs possess and be pharmacologically and physiologically inactive metabolites (see, Acta Physiologica Scandinavica, 66, p.509-(1966)).
It has been found that PGs in which the number of the carbon atom in the w-chain is increased, for instance, PGs in which the carbon atom of the 20-position is substituted with a hydrocarbon group (referred to as 20-substituted PGs hereinafter) or 15-keto-PGs in which the carbon atom of the 20-position is substituted with a hydrocarbon group (referred to as 20-substituted-15-keto-PGs hereinafter) cause intraocular pressure reduction without any transient ocular hypertensive response that PGs usually show. Further, they possess enhanced ocular hypotensive potency, and exhibit ocular hypotensive effect without transient ocular hypertensive response, and with absolutely no or extremely reduced side effects such as hyperemia of conjunctiva or of iris, dacryops, lema, closed eye and the like.
It has been found the above 13,14-dihydro-15-keto PGs (metabolites) cause intraocular pressure reduction without any transient ocular hypertensive response that PGs usually show. Further, among 13,14-dihydro-15-keto-PGs, or carboxylic acid, salts, esters, compounds having a 2,3-double bond, or a 5,6-triple bond, or compounds having substituents at any of C-3, C-6, C-16, C-17, C-19 and/or C-20 positions, compounds having a lower alkyl or hydroxyalkyl group at the C-9 and/or C-11 position instead of the hydroxyl group, possess enhanced ocular hypotensive potency, and these 13,14-dihydro-15-keto-PGs may exhibit ocular hypotensive effect without transient ocular hypertensive response, and with absolutely no or extremely reduced side effects such as hyperemia. Further, we have found that these 13,14-dihydro-15-keto-PGs are accompanied with no or extremely reduced peculiar central and peripheral physiological activities which are simultaneously caused by PGs, and further they have no effects on enteron, trachea or bronchus which are characteristic of PGs.